KR20140076979A - Solid dispersion with improved solubility comprising tetrazole derivative as an active ingredient - Google Patents

Solid dispersion with improved solubility comprising tetrazole derivative as an active ingredient Download PDF

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KR20140076979A
KR20140076979A KR1020120145603A KR20120145603A KR20140076979A KR 20140076979 A KR20140076979 A KR 20140076979A KR 1020120145603 A KR1020120145603 A KR 1020120145603A KR 20120145603 A KR20120145603 A KR 20120145603A KR 20140076979 A KR20140076979 A KR 20140076979A
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acid
solid dispersion
active ingredient
weight
amorphous solid
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KR101986683B1 (en
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김용일
최준영
최영근
박재현
우종수
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한미약품 주식회사
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Priority to KR1020120145603A priority Critical patent/KR101986683B1/en
Priority to ARP130104460A priority patent/AR093706A1/en
Priority to JOP/2013/0361A priority patent/JO3534B1/en
Priority to MYPI2015701648A priority patent/MY174746A/en
Priority to TW102145931A priority patent/TWI652073B/en
Priority to DK13863463.9T priority patent/DK2931720T3/en
Priority to SI201331462T priority patent/SI2931720T1/en
Priority to JP2015547856A priority patent/JP6355645B2/en
Priority to UY0001035186A priority patent/UY35186A/en
Priority to SG11201504067SA priority patent/SG11201504067SA/en
Priority to PE2015000908A priority patent/PE20151066A1/en
Priority to PL13863463T priority patent/PL2931720T3/en
Priority to PT13863463T priority patent/PT2931720T/en
Priority to PCT/KR2013/011545 priority patent/WO2014092489A1/en
Priority to HUE13863463 priority patent/HUE044659T2/en
Priority to RU2015128002A priority patent/RU2662819C2/en
Priority to TR2019/08746T priority patent/TR201908746T4/en
Priority to LTEP13863463.9T priority patent/LT2931720T/en
Priority to MX2015006416A priority patent/MX363644B/en
Priority to BR112015013905A priority patent/BR112015013905A2/en
Priority to ES13863463T priority patent/ES2731806T3/en
Priority to EP13863463.9A priority patent/EP2931720B1/en
Priority to NZ709071A priority patent/NZ709071A/en
Priority to CA2892376A priority patent/CA2892376C/en
Priority to US14/439,735 priority patent/US9283218B2/en
Priority to CN201380064980.5A priority patent/CN104870443B/en
Priority to AU2013360544A priority patent/AU2013360544B2/en
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Priority to ZA2015/03795A priority patent/ZA201503795B/en
Priority to DO2015000128A priority patent/DOP2015000128A/en
Priority to CL2015001551A priority patent/CL2015001551A1/en
Priority to SA515360535A priority patent/SA515360535B1/en
Priority to PH12015501312A priority patent/PH12015501312A1/en
Priority to IL239327A priority patent/IL239327A/en
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Abstract

The present invention relates to an amorphous solid dispersion containing a tetrazole derivative represented by chemical formula 1 or pharmaceutically acceptable salt thereof as an active ingredient. The solid dispersion of the present invention comprises water soluble polymers or acidic substances so as to improve the solubility of the tetrazole derivative, the active ingredient represented by the chemical formula 1, and improve the rate of absorption of the solid dispersion, thereby being effectively used for inhibiting multiple antibiotic resistance.

Description

테트라졸 유도체를 활성 성분으로 포함하는 용해도가 개선된 고체 분산체{SOLID DISPERSION WITH IMPROVED SOLUBILITY COMPRISING TETRAZOLE DERIVATIVE AS AN ACTIVE INGREDIENT}SOLID DISPERSION WITH IMPROVED SOLUBILITY COMPRISING TETRAZOLE DERIVATIVE AS AN ACTIVE INGREDIENT CONTAINING TETRAZOLE DERIVATIVES AS ACTIVE INGREDIENTS [0002]

본 발명은 테트라졸 유도체를 활성 성분으로 포함하는 용해도가 개선된 고체 분산체에 관한 것으로서, 보다 상세하게는 화학식 1의 테트라졸 유도체 또는 이의 약학적으로 허용가능한 염을 활성 성분으로 포함하는 무정형의 고체 분산체, 및 이를 포함하는 약학적 조성물에 관한 것이다.
The present invention relates to a solubility-improved solid dispersion comprising a tetrazole derivative as an active ingredient, and more particularly to a solid dispersion containing a tetrazole derivative of the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, A dispersion, and a pharmaceutical composition containing the same.

하기 화학식 1의 테트라졸 유도체 및 이의 약학적으로 허용 가능한 염은 암세포의 다약제 내성에 대한 저해 활성을 갖는 p-당단백질 저해제로 알려져 있다(국내 등록 특허 제10-0557093호 참조). The tetrazole derivatives of the following formula (I) and pharmaceutically acceptable salts thereof are known as p-glycoprotein inhibitors having an inhibitory activity against multidrug resistance of cancer cells (refer to Korean Patent No. 10-0557093).

<화학식 1>&Lt; Formula 1 >

Figure pat00001
Figure pat00001

(상기 식에서, R1 내지 R11, m, n 및 X는 이하에서 정의된 것과 동일하다.)
Wherein R 1 to R 11 , m, n and X are the same as defined below.

p-당단백질은 장의 내피세포 등에 존재하고 특정 약물의 경구흡수를 방해하는 것으로 알려져 있다. 주요 항암제인 파클리탁셀, 도세탁셀 등은 경구로 투여되었을 때, p-당단백질의 작용에 의해 대부분 흡수되지 않는다(Schinkel et al ., Cell, 77, 491-502, 1994). 또한 항암제 치료의 가장 심각한 문제점은 항암제에 대한 암세포의 내성 발현이며, 이중 p-당단백질의 과발현에 의한 다약제 내성(multi-drug resistance, MDR)이 가장 문제가 되고 있다. 암세포의 다약제 내성은 일반적으로 항암제의 사용에 따라 증가하며 이는 암 치료율을 현저히 낮추는 원인이 된다. p-glycoprotein is known to reside in the endothelial cells of the intestine and interfere with the oral absorption of certain drugs. Major anticancer drugs such as paclitaxel, docetaxel, etc., are mostly not absorbed by the action of p-glycoprotein when administered orally (Schinkel et al . , Cell , 77, 491-502, 1994). In addition, the most serious problem of anticancer drug treatment is the expression of cancer cell resistance against an anticancer drug, and multi-drug resistance (MDR) due to overexpression of p-glycoprotein is the most problematic. Multidrug resistance of cancer cells generally increases with the use of anticancer drugs, which causes the cancer treatment rate to be significantly lowered.

이에 따라 화학식 1의 테트라졸 유도체를 포함하는 p-당단백질 저해제는 상기와 같은 p-당단백질의 작용을 억제시킴으로써 특정 약물의 경구 투여를 가능하게 하고, p-당단백질 과발현에 의한 암세포의 다약제 내성(MDR)에 효과가 있을 것으로 기대되고 있다.Accordingly, the p-glycoprotein inhibitor comprising a tetrazole derivative of formula (I) inhibits the action of the p-glycoprotein described above, thereby enabling oral administration of a specific drug, It is expected that it will be effective for resistance (MDR).

그럼에도 불구하고, 상기 테트라졸 유도체 및 이의 약학적으로 허용가능한 염은 용해도가 매우 낮아 생체 내에서 높은 흡수를 기대하기 어렵다. 따라서, 상기 약물의 용해도 및 생체 흡수율을 개선할 수 있는 방안이 요구된다.
Nevertheless, the tetrazole derivatives and their pharmaceutically acceptable salts have very low solubility and are not expected to have high absorption in vivo. Accordingly, there is a need for a method for improving the solubility and the bioabsorption rate of the drug.

따라서, 본 발명의 목적은 전술한 테트라졸 유도체 및 이의 약학적으로 허용가능한 염의 용해도 및 그에 따른 생체 흡수율을 개선하는 것이다.
It is therefore an object of the present invention to improve the solubility and thus the bioavailability of the above-mentioned tetrazole derivatives and their pharmaceutically acceptable salts.

상기 목적을 달성하기 위해, 본 발명은 하기 화학식 1의 테트라졸 유도체 또는 이의 약학적으로 허용가능한 염을 활성 성분으로 포함하는 무정형의 고체 분산체를 제공한다:In order to achieve the above object, the present invention provides amorphous solid dispersion comprising a tetrazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

<화학식 1>&Lt; Formula 1 >

Figure pat00002
Figure pat00002

상기 식에서,In this formula,

R1은 비치환되거나 치환된 퀴놀린, 이소퀴놀린, 퀴녹살린, 피리딘, 피라진, 나프탈렌, 페닐, 티오펜, 퓨란, 4-옥소-4H-크로멘 또는 시놀린이고, 이때 치환체는 C1-C5 알킬, 하이드록시, C1-C5 알콕시, 할로겐, 트리플루오로메틸, 니트로 또는 아미노이며;And R 1 is unsubstituted or substituted quinoline, isoquinoline, quinoxaline, pyridine, pyrazine, naphthalene, phenyl, thiophene, furan, 4-oxo-chromene or -4H- when Quinoline, wherein the substituents are C 1 -C 5 Alkyl, hydroxy, C 1 -C 5 alkoxy, halogen, trifluoromethyl, nitro or amino;

R2 내지 R5 및 R8 내지 R11은 각각 독립적으로 수소, 하이드록시, 할로겐, 니트로, C1-C5 알킬 또는 알콕시이며, R6 및 R7은 각각 독립적으로 수소, 하이드록시, 할로겐, 니트로, C1-C5 알킬렌 또는 알콕시이고, 이 때, R6 및 R7은 연결되어 4 내지 8원 고리를 형성할 수 있으며;R 2 to R 5 and R 8 to R 11 are each independently hydrogen, hydroxy, halogen, nitro, C 1 -C 5 alkyl or alkoxy, R 6 and R 7 are each independently hydrogen, Nitro, C 1 -C 5 alkylene or alkoxy, wherein R 6 and R 7 may be connected to form a 4- to 8-membered ring;

m 및 n은 각각 독립적으로 0 내지 4 범위의 정수이고;m and n are each independently an integer ranging from 0 to 4;

X 는 CH2, 산소 또는 황 원자이다.
X is CH 2 , oxygen or sulfur atom.

본 발명의 고체 분산체는 수용성 고분자 및/또는 산성 물질을 포함함으로써 활성 성분인 화학식 1의 테트라졸 유도체의 용해도를 개선할 수 있으며, 이에 따라 상기 약물의 생체 흡수율을 개선할 수 있는바, 상기 다약제 내성을 저해하기 위한 용도로 유용하게 사용될 수 있다.
Since the solid dispersion of the present invention contains a water-soluble polymer and / or an acidic substance, solubility of the tetrazole derivative of the formula (1) as an active ingredient can be improved and the bioabsorption rate of the drug can be improved, And can be usefully used for inhibiting drug resistance.

도 1은 수용성 고분자의 함량을 달리하여 제조된, 화학식 1의 테트라졸 유도체인 HM30181A를 포함하는 고체 분산체(실시예 1 내지 6) 및 HM30181A 원말의 용해도를 나타낸 그래프이다.
도 2는 산성 물질 종류를 달리하여 제조된, HM30181A를 포함하는 고체 분산체(실시예 7 내지 13)의 용해도를 나타낸 그래프이다.
도 3은 HM30181A 원말의 X선 회절 패턴을 나타낸 것이다.
도 4는 실시예 8의 고체 분산체의 X선 회절 패턴을 나타낸 것이다.
도 5는 고체 분산체로부터 제조된 실시예 14의 정제 및 단순히 활성 성분을 혼합하여 제조된 비교예 1의 정제의 용출율을 나타낸 그래프이다.
FIG. 1 is a graph showing the solubilities of solid dispersions (Examples 1 to 6) and HM30181A containing HM30181A, which is a tetrazole derivative of Chemical Formula 1, prepared by varying the content of water-soluble polymer.
2 is a graph showing the solubilities of solid dispersions containing HM30181A (Examples 7 to 13) prepared by different kinds of acidic substances.
Fig. 3 shows an X-ray diffraction pattern of the HM30181A original.
4 shows an X-ray diffraction pattern of the solid dispersion of Example 8. Fig.
5 is a graph showing the dissolution rate of the tablets of Example 14 prepared from the solid dispersion and the tablets of Comparative Example 1 prepared by simply mixing the active ingredients.

이하 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.

본 발명은 전술한 화학식 1의 테트라졸 유도체 또는 이의 약학적으로 허용가능한 염을 활성 성분으로 포함하는 무정형의 고체 분산체를 제공한다.The present invention provides an amorphous solid dispersion comprising a tetrazole derivative of the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

상기 '화학식 1의 테트라졸 유도체 또는 이의 약학적으로 허용가능한 염', 이의 제조방법 및 이의 용도는 국내 특허 제10-0557093호에 개시되어 있다.
The 'tetrazole derivative of the formula 1 or a pharmaceutically acceptable salt thereof', a process for its preparation and its use are disclosed in Korean Patent No. 10-0557093.

본 발명의 하나의 구체예에서, 상기 테트라졸 유도체는 하기 화학식 2의 구조를 갖는 화합물(크로몬-2-카르복실산 [(2-(2-{4-[6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-페닐}-2H-테트라졸-5-일)-4,5-디메톡시페닐]아민 메실레이트) 또는 하기 화학식 3의 구조를 갖는 화합물(크로몬-2-카르복실산 [(2-(2-{4-[6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-페닐}-2H-테트라졸-5-일)-4,5-디메톡시페닐]아민)일 수 있다:In one embodiment of the present invention, the tetrazole derivative is a compound having the structure of the following formula (2) (Chromone-2-carboxylic acid [(2- (2- {4- [6,7-dimethoxy- , 4-dihydro-1H-isoquinolin-2-yl) -ethyl] -phenyl} -2H-tetrazol-5-yl) -4,5-dimethoxyphenyl] amine mesylate) Ethyl] - (2-hydroxy-2- [4- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin- Phenyl} -2H-tetrazol-5-yl) -4,5-dimethoxyphenyl] amine)

<화학식 2>(2)

Figure pat00003
Figure pat00003

<화학식 3> (3)

Figure pat00004
.
Figure pat00004
.

본 발명의 고체 분산체는 상기 화학식 1의 테트라졸 유도체 또는 이의 약학적으로 허용가능한 염을 용매, 바람직하게는 유기 용매에 용해시켜 혼합 용액을 형성한 후, 상기 용매를 통상의 방법, 바람직하게는 분무 건조(Spray drying)에 의해 제거함으로써 수득될 수 있다.
The solid dispersion of the present invention can be produced by dissolving the tetrazole derivative of the formula 1 or a pharmaceutically acceptable salt thereof in a solvent, preferably an organic solvent to form a mixed solution, Followed by removal by spray drying.

본 발명의 고체 분산체는 상기 활성 성분인 화학식 1의 테트라졸 유도체 또는 이의 약학적으로 허용가능한 염의 용해도를 개선하기 위한 목적으로, 상기 활성 성분 이외에 수용성 고분자 물질을 포함할 수 있다. The solid dispersion of the present invention may contain a water-soluble polymeric substance in addition to the active ingredient for the purpose of improving the solubility of the tetrazole derivative of the formula (1) or a pharmaceutically acceptable salt thereof.

상기 수용성 고분자 물질은 상기 테트라졸 유도체 또는 이의 약학적으로 허용가능한 염으로부터 고체 분산체를 제조할 때 수용성 담체로서 작용하여 활성 성분에 친수성을 부여함으로써 용해도를 향상시키고, 무정형 상태를 유지하는데 도움을 준다. 상기 수용성 고분자 물질의 예로는 히프로멜로오스, 하이드록시프로필셀룰로오스, 폴리비닐피롤리돈, 폴리비닐아세탈, 다이에틸아미노아세테이트, 폴리에틸렌글리콜 또는 이들의 혼합물을 들 수 있으나, 이에 제한되지는 않는다. 본 발명의 바람직한 구체예에서, 상기 테트라졸 유도체 또는 이의 약학적으로 허용가능한 염으로부터 고체 분산체를 제조할 때 히프로멜로오스가 사용된다. The water-soluble polymeric substance acts as a water-soluble carrier when the solid dispersion is prepared from the tetrazole derivative or a pharmaceutically acceptable salt thereof to impart hydrophilicity to the active ingredient, thereby improving the solubility and maintaining the amorphous state . Examples of the water-soluble polymeric substance include, but are not limited to, hypromellose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl acetal, diethylaminoacetate, polyethylene glycol, or mixtures thereof. In a preferred embodiment of the present invention, hypromellose is used when preparing the solid dispersion from the tetrazole derivative or a pharmaceutically acceptable salt thereof.

상기 수용성 고분자 물질은 활성 성분 1 중량부를 기준으로 0.1 내지 4 중량부의 양으로 포함될 수 있다. 수용성 고분자를 활성 성분 1 중량부를 기준으로 4 중량부까지 사용하는 경우 용해도를 향상시킬 수 있으나, 4 중량부를 초과하는 경우 고체 분산체의 겔화 정도가 심해져 활성 성분이 잘 방출되지 않는 문제가 발생할 수 있다.
The water-soluble polymer material may be contained in an amount of 0.1 to 4 parts by weight based on 1 part by weight of the active ingredient. When the water-soluble polymer is used up to 4 parts by weight based on 1 part by weight of the active ingredient, the solubility can be improved. However, when the water-soluble polymer is used in an amount of more than 4 parts by weight, the degree of gelation of the solid dispersion becomes severe, .

본 발명의 고체 분산체는 상기 활성 성분의 용해도를 개선하기 위한 목적으로, 전술한 활성 성분 이외에 산을 추가로 포함할 수 있다. 상기 산은 착염 혹은 주성분 주변의 미세 pH 조절 작용 등을 통해 활성 성분의 용해도를 향상시킬 수 있다. 본 발명의 고체 분산체를 제조할 때 사용될 수 있는 산의 예로는 인산, 염산, 황산, 질산, 아세트산, 붕산 등의 무기산; 및 구연산, 말산, 타르타르산, 주석산, 젖산, 사과산, 토실산, 호박산, 아스코르빈산, 글루타민산, 알긴산, 말레산, 아디프산 등의 유기산을 들 수 있으며, 사용된 산의 종류에 따라 용해도 개선 효과의 정도가 차이가 발생할 수 있다. 본 발명의 구체적인 예로는 인산, 말산, 구연산 및 타르타르산을 사용할 수 있다. 산은 활성 성분 1 중량부를 기준으로 0.1 내지 3 중량부의 양으로 포함될 수 있다.
The solid dispersion of the present invention may further contain an acid in addition to the above-mentioned active ingredient for the purpose of improving the solubility of the active ingredient. The acid can improve the solubility of the active ingredient through complexation or fine pH control around the main component. Examples of the acid which can be used in preparing the solid dispersion of the present invention include inorganic acids such as phosphoric acid, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, boric acid and the like; And organic acids such as citric acid, malic acid, tartaric acid, tartaric acid, lactic acid, malic acid, tosylic acid, succinic acid, ascorbic acid, glutamic acid, alginic acid, maleic acid and adipic acid. Depending on the type of acid used, The difference in the degree of difference between the two. Specific examples of the present invention include phosphoric acid, malic acid, citric acid and tartaric acid. The acid may be included in an amount of 0.1 to 3 parts by weight based on 1 part by weight of the active ingredient.

본 발명의 하나의 구체예에서, 화학식 1의 테트라졸 유도체 또는 이의 약학적으로 허용가능한 염을 활성 성분으로 포함하는 고체 분산체는 수용성 고분자 물질 및 산을 포함할 수 있다.
In one embodiment of the present invention, the solid dispersion comprising the tetrazole derivative of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient may comprise a water-soluble polymer material and an acid.

본 발명의 고체 분산체는 활성 성분을 염화메틸렌, 에탄올 및 정제수의 혼합 용매에 용해 및 분산시켜 제조될 수 있다. 상기 혼합 용매는 총 혼합 용매 1중량부에 대하여 염화메틸렌, 에탄올 및 정제수가 각각 0.5 내지 0.85 중량부, 0.1 내지 0.4 중량부 및 0.05 내지 0.2 중량부의 비율로 혼합되는 것이 바람직하다. 하나의 바람직한 구체예에서, 상기 혼합 용매는 염화메틸렌 : 에탄올 : 정제수 = 60~80 : 20~ 40 : 2~10의 중량 비율로 혼합될 수 있다. 또 다른 바람직한 구체예에서, 상기 혼합 용매는 염화메틸렌 : 에탄올 : 정제수 = 65 ~ 75 : 25 ~ 35 : 4 ~ 6의 중량 비율로 혼합될 수 있다. 상기 용매의 비율을 벗어나는 경우 용매의 층 분리가 발생하거나 주성분이 잘 용해되지 않는 문제가 발생할 수 있다.
The solid dispersion of the present invention can be prepared by dissolving and dispersing the active ingredient in a mixed solvent of methylene chloride, ethanol and purified water. Preferably, the mixed solvent is mixed with methylene chloride, ethanol, and purified water at a ratio of 0.5 to 0.85 parts by weight, 0.1 to 0.4 parts by weight, and 0.05 to 0.2 parts by weight, based on 1 part by weight of the total mixed solvent. In one preferred embodiment, the mixed solvent may be mixed in a weight ratio of methylene chloride: ethanol: purified water = 60-80: 20-40: 2-10. In another preferred embodiment, the mixed solvent may be mixed in a weight ratio of methylene chloride: ethanol: purified water = 65-75: 25-35: 4-6. If the proportion of the solvent is out of the range, separation of the solvent may occur or the main component may not dissolve well.

본 발명의 고체 분산체는 작은 입경 및 이에 따라 증가된 표면적을 갖는다. 본 발명의 고체 분산체는 150 μm 미만, 바람직하게는 100 μm 미만, 더욱 바람직하게는 40 μm 미만의 평균 입경을 갖는다.
The solid dispersion of the present invention has a small particle size and thus an increased surface area. The solid dispersion of the present invention has an average particle diameter of less than 150 μm, preferably less than 100 μm, more preferably less than 40 μm.

본 발명의 테트라졸 유도체는 수용성 고분자 물질 또는 산을 첨가하여 무정형의 고체 분산체로 제조됨으로써, 테트라졸 유도체의 용해도를 개선할 수 있으며, 이에 따라 상기 약물의 생체 흡수율을 크게 개선할 수 있다.
The tetrazole derivative of the present invention can be prepared as an amorphous solid dispersion by adding a water-soluble polymeric substance or an acid, thereby improving the solubility of the tetrazole derivative, thereby greatly improving the bioavailability of the drug.

본 발명은 전술한 고체 분산체를 포함하는 약학적 조성물을 제공한다. 상기 약학적 조성물은 단순히 화학식 1의 테트라졸 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 종래의 약학적 조성물에 비해 암세포의 다약제 내성을 저해하는 효과가 뛰어나다.
The present invention provides a pharmaceutical composition comprising the above-mentioned solid dispersion. The above pharmaceutical composition exerts an excellent effect of inhibiting multidrug resistance of cancer cells as compared to a conventional pharmaceutical composition comprising a tetrazole derivative of formula (I) or a pharmaceutically acceptable salt thereof.

또한, 본 발명에 따른 화학식 1의 테트라졸 유도체 또는 이의 염을 포함하는 고체 분산체는 항암제의 경구 흡수를 증가시키고, 암세포에 항암작용을 상승시킬 수 있어, 항암제와 함께 투여함으로써 항암제의 치료 효과를 강화시킬 수 있다. 그러므로, 본 발명에 따른 고체 분산체는 항암제에 내성을 가진 환자에게 항암제와 함께 투여함으로써 내성암을 치료할 수 있다.In addition, the solid dispersion containing the tetrazole derivative of the formula (I) or a salt thereof according to the present invention can increase the oral absorption of the anticancer agent and increase the anticancer effect on the cancer cell. Therefore, the therapeutic effect of the anticancer agent Can be strengthened. Therefore, the solid dispersion according to the present invention can treat endometrial cancer by administering it together with an anticancer agent to a patient having resistance to the anticancer agent.

본 발명에 따른 고체 분산체와 배합하여 사용하기에 적당한 항암제는 특별하게 제한되지 않으며, 바람직하게는 파클리탁셀(paclitaxel) 및 도세탁셀(docetaxel)과 같은 탁산계, 빈크리스틴(vincristine), 빈블라스틴(vinblastine) 및 빈노렐빈(vinorelbin)과 같은 빈카알카로이드계, 다우노마이신(daunomycin) 및 독소루비신(doxorubicin)과 같은 안트라사이클린계, 토포테칸(topotecan) 및 이리노테칸(irinotecan)과 같은 캠토데신계, 악티노마이신(actinomycin) 및 에토포시드(etopocid) 등의 항암제가 사용될 수 있다.
The anticancer agent suitable for use in combination with the solid dispersion according to the present invention is not particularly limited and is preferably selected from the group consisting of paclitaxel, docetaxel, vincristine, vinblastine, ), Vinca alkaloids such as vinorelbine, anthracycline based such as daunomycin and doxorubicin, camptothecin such as topotecan and irinotecan, actinomycin actinomycin) and etoposide (etopocide) can be used.

본 발명에 따른 약학 조성물은 통상적인 방법에 따라 제제화될 수 있으며, 정제, 환제, 산제, 캅셀제, 시럽, 에멀젼, 마이크로에멀젼 등의 다양한 경구 투여 형태 또는 근육내, 정맥내 또는 피하투여 주사제와 같은 비경구 투여 형태로 제조될 수 있다. 본 발명의 약학 조성물은 본 발명에 따른 고체 분산체, 임의의 가능한 담체 및 부형제를 포함할 수 있다. 본 발명의 약학 조성물이 경구제형의 형태로 제조되는 경우, 사용되는 담체 및 부형제의 예로는 셀룰로오스, 규산칼슘, 옥수수전분, 락토오스, 수크로스, 덱스트로스, 인산칼슘 및 스테아린산, 스테아린산마그네슘, 스테아린산칼슘, 젤라틴, 탈크, 계면활성제, 현탁제, 유화제, 희석제 등을 들 수 있다. 또한, 본 발명의 약학 조성물이 주사제의 형태로 제조되는 경우 사용되는 담체로는 물, 식염수, 포도당 수용액, 유사 당수용액, 알코올, 글리콜, 에테르(예, 폴리에틸렌글리콜 400), 오일, 지방산, 지방산에스테르, 글리세리드 또는 계면활성제, 현탁제, 유화제 등을 예로 들 수 있다. The pharmaceutical composition according to the present invention may be formulated according to a conventional method and may be formulated into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions or non-excipients such as intramuscular, intravenous or subcutaneous injections May be formulated in oral administration forms. The pharmaceutical compositions of the present invention may comprise a solid dispersion according to the present invention, any possible carrier and excipients. When the pharmaceutical composition of the present invention is prepared in the form of an oral preparation, examples of carriers and excipients used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate and stearic acid, magnesium stearate, calcium stearate, Gelatin, talc, a surfactant, a suspending agent, an emulsifying agent and a diluent. When the pharmaceutical composition of the present invention is prepared in the form of an injectable preparation, the carrier used may be water, saline solution, aqueous glucose solution, pseudosaccharide solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid, fatty acid ester , Glyceride or a surfactant, a suspending agent, and an emulsifying agent.

본 발명에 따른 고체 분산체를 포함하는 약학 조성물은 항암제 투여 전후에 각종 투여수단에 적합한 조제로서 단독으로 투여하거나, 하나 이상의 항암제와 배합하여 투여할 수 있다. 투여 유형은 치료할 환자의 증상, 항암제의 물리적 형태 등과 같은 다양한 인자에 따라 폭넓게 변할 수 있다.The pharmaceutical composition containing the solid dispersion according to the present invention may be administered alone or in combination with one or more anticancer drugs before or after administration of the anticancer drug as a preparation suitable for various administration means. The type of administration can vary widely depending on various factors such as the symptoms of the patient to be treated, the physical form of the anti-cancer agent, and the like.

본 발명의 고체 분산체는 항암제와 함께 병용하여 약제 내성을 반전시키기 위하여 일반적으로 성인에 대해 상기 테트라졸 유도체 또는 이의 염을 기준으로 하여 0.1 내지 100 mg/kg(체중) 범위의 양으로 경구 또는 비경구적 경로를 통해 투여될 수 있다.
The solid dispersion of the present invention may be administered either orally or parenterally in an amount ranging from 0.1 to 100 mg / kg (body weight) based on the tetrazole derivative or a salt thereof to an adult in order to reverse the drug resistance by using it in combination with an anti- May be administered via a quadratic route.

이하, 본 발명을 하기 실시예에 의하여 더욱 상세하게 설명한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들만으로 한정되는 것은 아니다. 이하, 본원에 사용된 용어 'HM30181A'는 국내 특허 제10-0557093호에 개시된 화학식 1의 화합물 중 하기 화학식 2의 화합물(크로몬-2-카르복실산 [(2-(2-{4-[6,7-디메톡시-3,4-디하이드로-1H-이소퀴놀린-2-일)-에틸]-페닐}-2H-테트라졸-5-일)-4,5-디메톡시페닐]아민 메실레이트)를 의미한다:Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Hereinafter, the term &quot; HM30181A &quot; as used herein refers to a compound of the following formula (2) (chronom-2-carboxylic acid [(2- (2- {4- [ 2-yl) -ethyl] -phenyl} -2H-tetrazol-5-yl) -4,5-dimethoxyphenyl] amine methanesulfonate Rate):

<화학식 2>(2)

Figure pat00005

Figure pat00005

실시예 1 내지 6 : 수용성 고분자 함량별 고체 분산체의 제조 Examples 1 to 6: Preparation of solid dispersion by water-soluble polymer content

표 1의 조성에 따라, 활성 성분으로서 HM30181A, 수용성 고분자 물질로서 히프로멜로오스(P-645) 및 부형제로서 규산을 염화메틸렌(MC), 에탄올(EtOH) 및 정제수(DW)의 혼합 용매에 완전히 용해 및 분산시킨 다음, 분무 건조기(Mini spray dryer B-290, Buchi, Switzerland)를 이용하여 분무 건조하여 실시예 1 내지 6의 고체 분산체를 제조하였다. (P-645) as a water-soluble polymer substance and silicic acid as an excipient were completely dissolved in a mixed solvent of methylene chloride (MC), ethanol (EtOH) and purified water (DW) Followed by spray drying using a spray dryer (Mini spray dryer B-290, Buchi, Switzerland) to prepare the solid dispersions of Examples 1 to 6.

성분ingredient 실시예 1Example 1 실시예 2Example 2 실시예 3Example 3 실시예 4Example 4 실시예 5Example 5 실시예 6Example 6 HM30181AHM30181A 150150 150150 150150 150150 150150 150150 히프로멜로오스
P-645Hypromellose
P-645 00 7575 150150 300300 450450 600600 규산(SiO2)Silicic acid (SiO 2) 00 150150 150150 150150 150150 150150 MC:EtOH:DW
(6.5:3.0:0.5, w/w)MC: EtOH: DW
(6.5: 3.0: 0.5, w / w) 90009000 90009000 90009000 90009000 90009000 90009000

실시예Example 7 내지 13 : 산성 물질 종류별 고체  7 to 13: Solids by type of acidic substance 분산체의Dispersion 제조 Produce

표 2의 조성에 따라, 활성 성분으로서 HM30181A, 산성 물질로서 인산, DL-말산, 구연산, L(+)-타르타르산, 푸마르산 또는 옥살산, 수용성 고분자 물질로서 히프로멜로오스(P-645)를 염화메틸렌, 에탄올 및 정제수의 혼합 용매에 완전히 용해 및 분산시킨 후 분무 건조하여 실시예 7 내지 13의 고체 분산체를 제조하였다. (P-645) as a water-soluble polymer substance was dissolved in methylene chloride (DMF) as an acidic substance, DL-malic acid, citric acid, L (+) - tartaric acid, fumaric acid or oxalic acid as an acidic substance, , Ethanol and purified water, followed by spray drying to prepare solid dispersions of Examples 7 to 13.

성분ingredient 실시예 7Example 7 실시예 8Example 8 실시예 9Example 9 실시예 10Example 10 실시예 11Example 11 실시예 12Example 12 실시예 13Example 13 HM30181AHM30181A 150150 150150 150150 150150 150150 150150 150150 인산Phosphoric acid 100100 150150 -- -- -- -- -- DL-말산DL-malic acid -- -- 300300 -- -- -- -- 구연산Citric acid -- -- -- 300300 -- -- -- L(+)-타르타르산L (+) - tartaric acid -- -- -- -- 300300 -- -- 푸마르산Fumaric acid -- -- -- -- -- 300300 -- 옥살산Oxalic acid -- -- -- -- -- -- 300300 히프로멜로오스
P-645Hypromellose
P-645 300300 300300 300300 300300 300300 300300 300300 MC:EtOH:DW (6.5:3.0:0.5, w/w)MC: EtOH: DW (6.5: 3.0: 0.5, w / w) 90009000 90009000 90009000 90009000 90009000 90009000 90009000

실시예Example 14 : 정제의 제조 14: Preparation of tablets

표 3의 조성에 따라, 활성 성분으로서 HM30181A, 산성 물질로서 인산, 수용성 고분자 물질로서 히프로멜로오스(P-645)를 염화메틸렌, 에탄올 및 정제수의 혼합 용매에 완전히 용해 및 분산시킨 후 분무 건조하여 고체 분산체를 제조하였다.Phosphoric acid as an acidic substance and hypromellose (P-645) as a water-soluble polymer substance were completely dissolved and dispersed in a mixed solvent of methylene chloride, ethanol and purified water, spray-dried, To prepare a solid dispersion.

이후, 표 4의 조성에 따라 상기 고체 분산체에 부형제로서 D-만니톨, 붕해제로서 크로스포비돈, 부형제로서 경질 무수 규산 및 활택제로서 나트륨 스테아릴 푸마레이트를 혼합한 다음, 압축하여 실시예 14의 정제를 제조하였다. Thereafter, the solid dispersion was mixed with D-mannitol as an excipient, crospovidone as a disintegrant, light silicic anhydride as an excipient, and sodium stearyl fumarate as a lubricant in accordance with the composition shown in Table 4, Tablets were prepared.

성분ingredient 함량(mg/정제)Content (mg / tablet) HM30181AHM30181A 6060 인산Phosphoric acid 4040 히프로멜로오스 P-645Hypromellose P-645 6060

성분ingredient mg/정제mg / tablet 고체분산체Solid dispersion 160160 D-만니톨(SD200)D-mannitol (SD200) 325325 크로스포비돈Crospovidone 5050 경질 무수규산Light anhydrous silicic acid 55 나트륨 스테아릴 푸마레이트Sodium stearyl fumarate 1010

비교예Comparative Example 1 : 정제의 제조 1: Preparation of tablets

표 5의 조성에 따라, 활성 성분으로서 HM30181A, 산성 가용화제로서 인산, 수용성 고분자 담체로서 히프로멜로오스(P-645), 부형제로서 D-만니톨, 붕해제로서 크로스포비돈, 부형제로서 경질 무수 규산 및 활택제로서 나트륨 스테아릴 푸마레이트를 혼합한 다음, 압축하여 비교예 1의 정제를 제조하였다. (P-645) as a water-soluble polymer carrier, D-mannitol as an excipient, crospovidone as a disintegrant, light silicic anhydride as an excipient, and water as an excipient, as the active ingredient, Sodium stearyl fumarate was mixed as a lubricant, and then compressed to prepare tablets of Comparative Example 1.

성분ingredient mg/정제mg / tablet HM30181AHM30181A 6060 인산Phosphoric acid 4040 히프로멜로오스 P-645Hypromellose P-645 6060 D-만니톨(SD200)D-mannitol (SD200) 325325 크로스포비돈Crospovidone 5050 경질 무수규산Light anhydrous silicic acid 55 나트륨 스테아릴 푸마레이트Sodium stearyl fumarate 1010

실험예Experimental Example 1: 용매에 따른 활성 성분의 용해도 측정 1: Determination of solubility of active ingredient with solvent

고체 분산체의 제조를 위한 최적의 용매를 선정하기 위하여, 활성 성분인 HM30181A를 과량 취하여 일정량의 용매에 넣고 2시간 진탕한 후, 이를 원심분리하여 상층액을 HPLC로 분석하여 용해도를 측정하였다. 시험 용매로, 염화메틸렌, 메탄올, 에탄올, 헥산, 디에틸에테르, 이소프로필알코올, 아세톤 및 정제수를 사용하였다. 상기 측정 결과를 표 6에 나타내었다. In order to select the optimal solvent for the preparation of the solid dispersion, an excess of HM30181A as an active ingredient was taken in a certain amount of solvent and shaken for 2 hours. The HM30181A was centrifuged and the supernatant was analyzed by HPLC to measure its solubility. As test solvents, methylene chloride, methanol, ethanol, hexane, diethyl ether, isopropyl alcohol, acetone and purified water were used. The measurement results are shown in Table 6.

용매 menstruum 용해도(ppm)Solubility (ppm) 염화메틸렌Methylene chloride 6848.286848.28 메탄올Methanol 10177.5010177.50 에탄올ethanol 382.63382.63 헥산Hexane 0.050.05 디에틸에테르Diethyl ether 0.000.00 이소프로필알코올Isopropyl alcohol 31.2931.29 아세톤Acetone 9.239.23 정제수 Purified water 0.000.00

상기 표 6에서 보는 바와 같이, 테트라졸 유도체인 HM30181A는 대부분의 용매에 대하여 낮은 용해도를 나타내었다. 이는 상기와 같이 단일 용매를 사용할 경우 고체 분산체의 제조시 활성 성분의 가용화를 위해 상당히 많은 양의 용매가 필요하다는 것을 의미하며, 이로 인해 생산성 악화와 생산비용 증가를 초래할 수 있다.
As shown in Table 6, HM30181A, a tetrazole derivative, exhibited low solubility for most of the solvents. This means that when a single solvent is used as described above, a considerably large amount of solvent is required for solubilizing the active ingredient in the production of the solid dispersion, which may lead to deterioration of productivity and increase of production cost.

한편, 상기 개별 용매에 대한 실험에서 상대적으로 높은 용해도를 나타낸 염화메틸렌과 에탄올을 조합하여 용해 양상을 검토하였다. 상기 실험에서 메탄올은 높은 용해도를 보였으나, 독성 문제로 제외시켰다. 상기 측정 결과를 표 7에 나타내었다. On the other hand, the dissolution profile of methylene chloride and ethanol, which showed a relatively high solubility in the above-mentioned individual solvents, was examined. In this experiment, methanol was shown to be highly soluble but was excluded due to toxicity. The measurement results are shown in Table 7.

　 HM30181AHM30181A 염화메틸렌Methylene chloride 에탄올ethanol 정제수Purified water 용해 성상Dissolution property 용해도
(ppm)Solubility
(ppm) 조성 1 (mg)Composition 1 (mg) 1515 450450 5050 00 불투명opacity 10,26010,260 조성 2 (mg)Composition 2 (mg) 1515 350350 150150 00 불투명opacity 20,37020,370 조성 3 (mg)Composition 3 (mg) 1515 250250 250250 00 불투명opacity 4,7104,710 조성 4 (mg)Composition 4 (mg) 1515 450450 5050 2525 용매 층분리Solvent layer separation -- 조성 5 (mg)　Composition 5 (mg) 1515 350350 150150 2525 투명Transparency 27,85027,850

상기 표에서 보는 바와 같이, 염화메틸렌과 에탄올을 혼합하는 것보다 여기에 정제수를 추가로 포함시키는 것이 활성 성분을 투명하게 가용화하는데 적합한 것으로 확인되었다. 또한, 본 발명이 고체 분산체를 제조하기 위한 최적의 용매 조성이 염화메틸렌 : 에탄올 : 정제수 = 70: 30 :5의 중량 비율임을 알 수 있었다.
As shown in the above table, it was confirmed that addition of purified water to the mixture of methylene chloride and ethanol was suitable for transparent solubilization of the active ingredient. In addition, it was found that the optimal solvent composition for producing the solid dispersion of the present invention was a weight ratio of methylene chloride: ethanol: purified water = 70: 30: 5.

실험예Experimental Example 2: 수용성 고분자 첨가에 따른 고체  2: Solids due to addition of water-soluble polymer 분산체의Dispersion 용해도 측정 Solubility measurement

실시예 1 내지 6에서 제조된 고체 분산체를 각각 HM30181A로서 150 mg에 상응하는 양을 취하여 다음과 같은 조건에서 용출시켜 그 용해도를 비교하였다.The solid dispersions prepared in Examples 1 to 6 were each extracted as HM30181A in an amount corresponding to 150 mg, and their solubilities were compared by eluting under the following conditions.

- 용출 시험 조건-- Elution test conditions -

① 시험액 : 정제수 900 mL① Test solution: 900 mL of purified water

② 장치 : 회전검체통, 100 rpm② Device: Rotating sample bottle, 100 rpm

③ 온도 : 37℃③ Temperature: 37 ℃

-분석 조건-- Analysis conditions -

① 컬럼 : 내경이 약 4.6 mm이고 길이가 15 cm인 스테인레스 관에 입경 5 μm의 액체 크로마토그래프용 옥타데실실릴화된 실리카 겔이 충전된 컬럼Column: A column filled with octadecylsilylated silica gel for a liquid chromatograph having a diameter of 5 μm in a stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm

② 이동상 : 아세토니트릴: pH 2.5 완충용액 (56:44)Mobile phase: acetonitrile: pH 2.5 buffer solution (56:44)

③ 칼럼온도 : 40℃③ Column temperature: 40 캜

④ 유 속 : 1.0 mL/분④ Flow rate: 1.0 mL / min

⑤ 주입량 : 10 μL⑤ Injection amount: 10 μL

* pH 2.5 완충용액: 과염소산나트륨(NaClO4) 7.0 g 및 인산이수소칼륨(KH2PO4) 1.7 g을 정제수 900 mL에 녹인 다음 인산으로 pH를 2.5로 조정한 후 정제수로 1L를 맞춤.* pH 2.5 buffer solution: 7.0 g of sodium perchlorate (NaClO 4 ) and 1.7 g of potassium dihydrogen phosphate (KH 2 PO 4 ) are dissolved in 900 mL of purified water. The pH is adjusted to 2.5 with phosphoric acid, and 1 L is added to purified water.

실시예 1 내지 6의 고체 분산체의 용해도 측정 결과를 도 1에 나타내었다. 도 1에서 보는 바와 같이, 원말(활성 성분 자체)의 경우 거의 용해되지 않았으나, 수용성 고분자인 히프로멜로오스(P-645)를 첨가하는 경우 고체 분산체의 용해도가 증가하였다. 또한, 상기 수용성 고분자의 함량이 증가할수록 고체 분산체의 용해도도 증가하는 경향을 나타내었다. 특히, 수용성 고분자를 활성 성분 대비 4배까지 증량시키는 경우 용해도가 개선되었으나, 4배를 초과하여 사용하는 경우 제조된 고체 분산체의 겔화 정도가 심해져 활성 성분이 잘 방출되지 않는 문제가 발생하였다. The solubility measurement results of the solid dispersions of Examples 1 to 6 are shown in Fig. As shown in FIG. 1, the solubility of the solid dispersion was increased when the water-soluble polymer (P-645) was added while the raw material (active ingredient itself) was hardly dissolved. In addition, the solubility of the solid dispersion tends to increase as the content of the water soluble polymer increases. In particular, when the water-soluble polymer is increased up to 4 times as much as the active ingredient, the solubility is improved. However, when the water-soluble polymer is used in excess of 4 times, the degree of gelation of the prepared solid dispersion is increased.

상기 결과로부터, 본 발명의 고체 분산체를 제조하기 위한 최적의 수용성 고분자 함량이 활성 성분 1 중량부를 기준으로 0.1 내지 4 중량부 범위임을 확인할 수 있었다.
From the above results, it was confirmed that the optimum water-soluble polymer content for producing the solid dispersion of the present invention ranged from 0.1 to 4 parts by weight based on 1 part by weight of the active ingredient.

실험예Experimental Example 3: 산성 물질 첨가에 따른 고체  3: solid due to addition of acidic substance 분산체의Dispersion 용해도 측정 Solubility measurement

실시예 7 내지 13에서 제조된 고체 분산체를 각각 HM30181A로서 150 mg에 상응하는 양을 취하여 실험예 2와 같은 조건 하에서 용해도를 비교하였다. 상기 측정 결과를 도 2에 나타내었다. Solubilities of the solid dispersions prepared in Examples 7 to 13 were compared with those of Experimental Example 2 by taking amounts corresponding to 150 mg as HM30181A, respectively. The measurement results are shown in Fig.

도 2에서 보는 바와 같이, 특히 산성 물질로서 인산(실시예 7 및 8) 및 DL-말산(실시예 9)을 사용하여 제조된 고체 분산체의 경우, HM30181A로서 150 mg이 정제수 900 mL에 모두 용해되었으며, 상기 용해된 상태가 24시간 이상 유지되어 우수한 용해도를 나타내었다(도면에는 6시간까지만 표시함). 또한, 산성 물질로서 구연산(실시예 10) 및 L(+)-타르타르산을 사용하여 제조된 고체 분산체의 경우, HM30181A로서 약 130 mg 정도가 정제수 900 mL에 용해되어 우수한 용해도를 나타내었다.
As shown in FIG. 2, in the case of the solid dispersion prepared using phosphoric acid (Examples 7 and 8) and DL-malic acid (Example 9) as acidic substances, 150 mg as HM30181A was dissolved in 900 mL of purified water , And the dissolved state was maintained for more than 24 hours, indicating excellent solubility (only up to 6 hours in the figure). In addition, in the case of the solid dispersion prepared by using citric acid (Example 10) and L (+) - tartaric acid as the acidic substance, about 130 mg of HM30181A was dissolved in 900 mL of purified water, showing excellent solubility.

실험예 4: 활성 성분 및 이를 포함하는 고체 분산체의 결정 형태 분석Experimental Example 4: Analysis of crystalline form of active ingredient and solid dispersion containing the same

활성 성분인 HM30181A 원말 및 실시예 8의 고체 분산체의 결정 형태를 X선 회절(X-ray diffraction) 분석기(M18XHF-SRA, Macscience Co., LTD, Japan)를 사용하여 Cu X-선, 40 kV, 100 mA, 스캔 속도 6 deg/분의 조건 하에 분석하였다. The crystal form of the HM30181A raw material as the active ingredient and the solid dispersion of Example 8 was analyzed by X-ray diffraction analyzer (M18XHF-SRA, Macscience Co., LTD, Japan) using Cu X-ray, 40 kV , 100 mA, and a scan rate of 6 deg / min.

HM30181A 및 실시예 8의 고체 분산체의 X선 회절 패턴 측정 결과를 각각 도 3 및 도 4에 나타내었다. 도 3에서 보는 바와 같이 활성 성분인 HM30181A 원말은 2theta degree 4.911, 6.474, 7.948, 9.827, 10.712, 11.522, 12.007, 12.936, 13.498, 14.063, 14.744, 15.282, 15.878, 16.686, 18.66, 19.388, 19.698, 21.065, 23.22, 25.222, 26.485, 26.86, 28.405에서 피크를 나타내었으나, 도 4에서 보는 바와 같이 이를 포함한 고체 분산체는 분무 건조를 통해 무정형으로 변화하였음을 알 수 있었다.
The results of X-ray diffraction pattern measurement of HM30181A and the solid dispersion of Example 8 are shown in Fig. 3 and Fig. 4, respectively. As shown in FIG. 3, the active ingredient HM30181A was found to have 2theta degree of 4.911, 6.474, 7.948, 9.827, 10.712, 11.522, 12.007, 12.936, 13.498, 14.063, 14.744, 15.282, 15.878, 16.686, 18.66, 19.388, 19.698, 23.22, 25.222, 26.485, 26.86, and 28.405, respectively. As shown in FIG. 4, it was found that the solid dispersion containing the same changed into amorphous form through spray drying.

실험예 5: 고체 분산체의 입도 평가Experimental Example 5: Evaluation of particle size of solid dispersion

실시예 1 내지 13의 고체 분산체의 평균 입도를 레이저 회절(Laser diffraction) 입도측정기인 HELOS/BR(SYPATEC, Germany)을 사용하여 R1 렌즈로 4.5 bar의 조건으로 측정하였다. The average particle sizes of the solid dispersions of Examples 1 to 13 were measured by a laser diffraction particle size analyzer HELOS / BR (SYPATEC, Germany) under conditions of 4.5 bar with an R1 lens.

평균 입도 측정 결과를 하기 표 8에 나타내었다. The average particle size measurement results are shown in Table 8 below.

평균 입도Average particle size 실시예 1Example 1 8 μm8 μm 실시예 2Example 2 21 μm21 μm 실시예 3Example 3 18 μm18 μm 실시예 4Example 4 30 μm30 μm 실시예 5Example 5 25 μm25 μm 실시예 6Example 6 33 μm33 μm 실시예 7Example 7 23 μm23 μm 실시예 8Example 8 26 μm26 μm 실시예 9Example 9 31 μm31 μm 실시예 10Example 10 29 μm29 μm 실시예 11Example 11 27 μm27 μm 실시예 12Example 12 23 μm23 μm 실시예 13Example 13 21 μm21 μm

상기 표에서 보는 바와 같이, 실시예 1 내지 13의 고체 분산체는 30 μm 이하의 평균 입도를 가짐을 확인할 수 있었다.
As shown in the table, it was confirmed that the solid dispersions of Examples 1 to 13 had an average particle size of 30 μm or less.

실험예Experimental Example 6: 정제의 용출 분석 6: Analysis of elution of tablets

비교예 1 및 실시예 14에서 제조된 정제를 다음과 같은 조건에서 용출시켜 그 용해도를 비교하였다.The tablets prepared in Comparative Example 1 and Example 14 were eluted under the following conditions to compare their solubilities.

- 용출 시험 조건-- Elution test conditions -

① 시험액 : 정제수 900 mL① Test solution: 900 mL of purified water

② 장치 : 패들, 100 rpm② Device: paddle, 100 rpm

③ 온도 : 37℃③ Temperature: 37 ℃

-분석 조건-- Analysis conditions -

시험예 2의 분석 조건과 동일
Same as the analysis conditions of Test Example 2

상기 측정 결과를 도 5에 나타내었다. 도 5에서 보는 바와 같이, 고체 분산체로부터 제조된 실시예 14의 정제의 경우 15분 이내에 완전히 용출이 이루어지는데 반해, 단순히 활성 성분을 혼합하여 제조된 비교예 1의 정제의 경우 시간이 지나도 전혀 용출이 이루어지지 않았다. 상기 결과는 본 발명의 테트라졸 유도체는 부형제와 단순 혼합한 정제로는 용해도를 개선시킬 수 없으며, 고체 분산체를 통해 용해도를 개선시킬 수 있음을 보여준다.The measurement results are shown in Fig. As shown in FIG. 5, in the case of the tablets of Example 14 prepared from the solid dispersion, the tablets completely eluted within 15 minutes, whereas the tablet of Comparative Example 1, which was prepared by simply mixing the active ingredients, . The results show that the tetrazole derivative of the present invention can not improve the solubility by simple mixing with the excipient and can improve solubility through the solid dispersion.

Claims (14)

하기 화학식 1의 테트라졸 유도체 또는 이의 약학적으로 허용가능한 염을 활성 성분으로 포함하는 무정형의 고체 분산체:
<화학식 1>
Figure pat00006

상기 식에서,
R1은 비치환되거나 치환된 퀴놀린, 이소퀴놀린, 퀴녹살린, 피리딘, 피라진, 나프탈렌, 페닐, 티오펜, 퓨란, 4-옥소-4H-크로멘 또는 시놀린이고, 이때 치환체는 C1-C5 알킬, 하이드록시, C1-C5 알콕시, 할로겐, 트리플루오로메틸, 니트로 또는 아미노이며;
R2 내지 R5 및 R8 내지 R11은 각각 독립적으로 수소, 하이드록시, 할로겐, 니트로, C1-C5 알킬 또는 알콕시이며, R6 및 R7은 각각 독립적으로 수소, 하이드록시, 할로겐, 니트로, C1-C5 알킬렌 또는 알콕시이고, 이 때, R6 및 R7은 연결되어 4 내지 8원 고리를 형성할 수 있으며;
m 및 n은 각각 독립적으로 0 내지 4 범위의 정수이고;
X 는 CH2, 산소 또는 황 원자이다.
An amorphous solid dispersion comprising a tetrazole derivative of the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
&Lt; Formula 1 >
Figure pat00006

In this formula,
And R 1 is unsubstituted or substituted quinoline, isoquinoline, quinoxaline, pyridine, pyrazine, naphthalene, phenyl, thiophene, furan, 4-oxo-chromene or -4H- when Quinoline, wherein the substituents are C 1 -C 5 Alkyl, hydroxy, C 1 -C 5 alkoxy, halogen, trifluoromethyl, nitro or amino;
R 2 to R 5 and R 8 to R 11 are each independently hydrogen, hydroxy, halogen, nitro, C 1 -C 5 alkyl or alkoxy, R 6 and R 7 are each independently hydrogen, Nitro, C 1 -C 5 alkylene or alkoxy, wherein R 6 and R 7 may be connected to form a 4- to 8-membered ring;
m and n are each independently an integer ranging from 0 to 4;
X is CH 2 , oxygen or sulfur atom.
제1항에 있어서, 상기 테트라졸 유도체가 하기 화학식 2 또는 화학식 3의 구조를 갖는 것을 특징으로 하는 무정형의 고체 분산체:
<화학식 2>
Figure pat00007

<화학식 3>
Figure pat00008
.
The amorphous solid dispersion according to claim 1, wherein the tetrazole derivative has a structure represented by the following formula (2) or (3):
(2)
Figure pat00007

(3)
Figure pat00008
.
제1항에 있어서, 상기 고체 분산체가 수용성 고분자 물질을 포함하는 것을 특징으로 하는 무정형의 고체 분산체.
The amorphous solid dispersion according to claim 1, wherein the solid dispersion comprises a water-soluble polymer material.
제3항에 있어서, 상기 수용성 고분자 물질이 히프로멜로오스, 하이드록시프로필셀룰로오스, 폴리비닐피롤리돈, 폴리비닐아세탈, 다이에틸아미노아세테이트, 폴리에틸렌글리콜 및 이들의 혼합물로 이루어진 군으로부터 선택되는 것을 특징으로 하는 무정형의 고체 분산체.
The method of claim 3, wherein the water-soluble polymer material is selected from the group consisting of hypromellose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl acetal, diethylaminoacetate, polyethylene glycol, and mixtures thereof Of an amorphous solid dispersion.
제3항에 있어서, 상기 수용성 고분자 물질이 활성 성분 1 중량부를 기준으로 0.1 내지 4 중량부의 양으로 포함되는 것을 특징으로 하는 무정형의 고체 분산체.
4. The amorphous solid dispersion according to claim 3, wherein the water-soluble polymer material is contained in an amount of 0.1 to 4 parts by weight based on 1 part by weight of the active ingredient.
제1항에 있어서, 상기 고체 분산체가 산을 포함하는 것을 특징으로 하는, 무정형의 고체 분산체.
The amorphous solid dispersion according to claim 1, wherein the solid dispersion comprises an acid.
제6항에 있어서. 상기 산이 인산, 염산, 황산, 질산, 아세트산 및 붕산으로부터 선택되는 무기산; 및 구연산, 말산, 타르타르산, 주석산, 젖산, 사과산, 토실산, 호박산, 아스코르빈산, 글루타민산, 알긴산, 말레산 및 아디프산으로부터 선택되는 유기산으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 무정형의 고체 분산체.
The method of claim 6, An inorganic acid selected from the group consisting of phosphoric acid, hydrochloric acid, sulfuric acid, nitric acid, acetic acid and boric acid; And an organic acid selected from citric acid, malic acid, tartaric acid, tartaric acid, lactic acid, malic acid, tosylic acid, succinic acid, ascorbic acid, glutamic acid, alginic acid, maleic acid and adipic acid. sieve.
제6항에 있어서, 상기 산이 활성 성분 1 중량부를 기준으로 0.1 내지 3 중량부의 양으로 포함되는 것을 특징으로 하는 무정형의 고체 분산체.
The amorphous solid dispersion according to claim 6, wherein the acid is contained in an amount of 0.1 to 3 parts by weight based on 1 part by weight of the active ingredient.
제1항에 있어서, 상기 고체 분산체가 용매로서 염화메틸렌 0.5 내지 0.85 중량부, 에탄올 0.1 내지 0.4 중량부 및 정제수 0.05 내지 0.2 중량부의 비율로 혼합된 혼합 용매를 이용하여 제조되는 것을 특징으로 하는 무정형의 고체 분산체.
2. The process according to claim 1, wherein the solid dispersion is prepared using a mixed solvent comprising 0.5 to 0.85 parts by weight of methylene chloride as a solvent, 0.1 to 0.4 parts by weight of ethanol and 0.05 to 0.2 parts by weight of purified water, Solid dispersion.
제1항에 있어서, 상기 고체 분산체가 150 μm 미만의 평균 입경을 갖는 것을 특징으로 하는 무정형의 고체 분산체.
2. The amorphous solid dispersion according to claim 1, wherein the solid dispersion has an average particle diameter of less than 150 mu m.
제1항의 고체 분산체를 포함하는 약학적 조성물.
A pharmaceutical composition comprising the solid dispersion of claim 1.
제11항에 있어서, 상기 약학적 조성물이 암세포의 다약제 내성을 저해하는 것을 특징으로 하는 약학적 조성물.
12. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition inhibits multidrug resistance of cancer cells.
제1항의 고체 분산체, 및 p-당단백질에 의해 경구흡수가 저해되는 항암제를 포함하는, 항암제의 경구흡수율 증가용 조성물.
A composition for increasing the oral absorption rate of an anticancer agent, which comprises the solid dispersion of claim 1 and an anticancer agent which is inhibited by oral absorption by p-glycoprotein.
제13항에 있어서, 상기 항암제가 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 빈크리스틴(vincristine), 빈블라스틴(vinblastine), 빈노렐(vinorelbin), 다우노마이신(daunomycin), 독소루비신(doxorubicin), 토포테칸(topotecan), 이리노테칸(irinotecan), 악티노마이신(actinomycin) 및 에토포시드(etopocid)로 이루어진 군으로부터 선택되는 것을 특징으로 하는 조성물.
14. The method of claim 13, wherein the anticancer agent is selected from the group consisting of paclitaxel, docetaxel, vincristine, vinblastine, vinorelbin, daunomycin, doxorubicin, Wherein the composition is selected from the group consisting of topotecan, irinotecan, actinomycin and etopocid.
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